3F7H

Structure of an ML-IAP/XIAP chimera bound to a peptidomimetic


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.175 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.150 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold

Cohen, F.Alicke, B.Elliott, L.O.Flygare, J.A.Goncharov, T.Keteltas, S.F.Franklin, M.C.Frankovitz, S.Stephan, J.P.Tsui, V.Vucic, D.Wong, H.Fairbrother, W.J.

(2009) J Med Chem 52: 1723-1730

  • DOI: https://doi.org/10.1021/jm801450c
  • Primary Citation of Related Structures:  
    3F7G, 3F7H, 3F7I

  • PubMed Abstract: 

    A series of IAP antagonists based on an azabicyclooctane scaffold was designed and synthesized. The most potent of these compounds, 14b, binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domain of c-IAP1 with K(i) values of 140, 38, and 33 nM, respectively. These compounds promote degradation of c-IAP1, activate caspases, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Finally, compound 14b inhibits tumor growth when dosed orally in a breast cancer xenograft model.


  • Organizational Affiliation

    Departments of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. fcohen@gene.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Baculoviral IAP repeat-containing protein 7
A, B
133Homo sapiensMutation(s): 11 
Gene Names: BIRC7KIAPLIVINMLIAPRNF50UNQ5800/PRO19607/PRO21344
UniProt & NIH Common Fund Data Resources
Find proteins for Q96CA5 (Homo sapiens)
Explore Q96CA5 
Go to UniProtKB:  Q96CA5
PHAROS:  Q96CA5
GTEx:  ENSG00000101197 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ96CA5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
419
Query on 419

Download Ideal Coordinates CCD File 
D [auth A],
G [auth B]
N-[(3aR,6S,6aS)-1-(N-methyl-L-alanyl-3-methyl-L-valyl)octahydrocyclopenta[b]pyrrol-6-yl]-2,2-diphenylacetamide
C31 H42 N4 O3
BGWQMUKSEXDJIL-PCVPZPMISA-N
BTB
Query on BTB

Download Ideal Coordinates CCD File 
H [auth B]2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL
C8 H19 N O5
OWMVSZAMULFTJU-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
I [auth B],
J [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
LI
Query on LI

Download Ideal Coordinates CCD File 
F [auth B]LITHIUM ION
Li
HBBGRARXTFLTSG-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
419 PDBBind:  3F7H Ki: 82 (nM) from 1 assay(s)
BindingDB:  3F7H Ki: 82 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.175 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.150 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.048α = 90
b = 88.048β = 90
c = 73.321γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-12-27
    Changes: Data collection